Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. Although treatment combining surgery, radiation and high-dose chemotherapy has led to increased survival rates, many MB patients still die from the disease. Moreover, surviving patients suffer severe long-term side effects as a consequence of treatment. It is therefore crucial to develop more effective and less toxic therapies. The most aggressive subtype of MB consists of tumors that exhibit amplification of the MYC oncogene. Patients with MYC-amplified MB exhibit a high frequency of tumor dissemination to the entire brain and spinal cord, often experience treatment resistance and have extremely poor prognoses. In this application, we propose to use novel mouse MYC-driven MB and patient-derived xenograft (PDX) models to investigate the role of oligodendrocyte lineage transcription factor 2 (Olig2) in tumorigenesis, progression and metastasis of MYC-amplified MB. We will use these mouse models to evaluate a novel targeted approach to treatment. To accomplish this we will: (1) evaluate whether ablation of Olig2+ tumor cells can prevent tumor formation, progression and metastasis, (2) determine whether deletion of the Olig2 gene prevents tumor progression and metastasis, and (3) test the prediction that targeting Olig2 with a small molecule inhibitor can inhibit growth and prevent metastasis in a human MYC-amplified MB PDX model. If these studies are successful, they will help identify new targeted therapies that can be effective in treating patients with MYC-amplified MB.